Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that applies weak electric currents to the head. tDCS is proposed to modulate cognitive function with few known side effects and is under investigation for the treatment of diverse neurological or psychiatric conditions such as pain, depression, and stroke. The conventional assumption for the mechanism of action of tDCS is that a positively charged electrode increases cortical 'excitability' and this 'enhances' function attributed to the targeted cortical area. However, this simplistic excitability assumption does not explain the diversity across studies and specificity within studies of reported cognitive effects, and has not been reliable at predicting outcomes of clinical trials. To guide and accelerate the development of new treatment protocols, it is important to clarify the cellular mechanisms of direct current stimulatin (DCS). We propose that DCS acts via a modulation of endogenous synaptic plasticity mechanisms. Support for this comes from pharmacological experiments in humans as well as direct evidence that DCS can boost synaptic plasticity in brain slices. The goal of this proposal is to determine the cellular mechanisms by which DCS modulates long-term synaptic plasticity. We have recently demonstrated robust effects of DCS on long-term potentiation (LTP) and long-term depression (LTD) using standard plasticity induction protocols such as tetanus and theta burst stimulation. We will probe well-established cellular mechanisms of these induction protocols in hippocampal slices, which provide unique control of the effects of stimulation on different cellular compartments. In Aim 1 we explore the specific hypothesis that DCS modulates LTP/LTD by polarizing dendrites directly affecting calcium dynamics through voltage dependent calcium channels. In Aim 2 we test the specific hypothesis that DCS modulates LTP by polarizing cell somata, thus modulating post-synaptic firing rate. A series of predictions that result from these specific hypotheses will be tested using two-photon calcium imaging, stimulation and recordings from multiple pathways, patch-clamp recordings, and pharmacological interventions to determine involvement of calcium and sodium channels as well as neuro-modulators such as brain-derived neurotropic factor (BDNF). Finally, all experimental results will be synthesized in biophysically realistic computational models. Our basic proposal provides a mechanistic explanation for observed functional specificity, because only networks undergoing plasticity are boosted by DCS. Importantly, if confirmed, our specific hypotheses link the mechanisms of DCS with well-established mechanisms of LTD/LTP, which are in turn linked to learning and disease. This has important clinical implications. For instance, it suggests that tDCS will be most effective as an adjunct to behavioral interventions that foster plasticity and it provides answers for clinically relevant questions such as how long the effects of tDCS persist. The results of this project will provide a precise and quantitative framework to understand the cellular mechanistic of DCS, which is required in order to advance the science and treatment of tDCS.